New label‐free automated survival assays reveal unexpected stress resistance patterns during <i>C. elegans</i> aging

Benedetto, Alexandre; Bambade, Timothee; Au, Catherine; Tullet, Jennifer M. A.; Monkhouse, Jennifer; Dang, Hairuo; Cetnar, Kalina; Chan, Brian H. K.; Cabreiro, Filipe

doi:10.1111/acel.12998

Cited by 18 publications

(28 citation statements)

References 60 publications

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“…Resistance to heat and oxidative stress was assessed by the label-free automated survival scoring (LFASS) approach, which relies on time-lapse measurements of blue death fluorescence (λ ex = 360 nm, λ em = 435 nm) [ 44 ]. For both assays, approximately 200 worms were placed per well in a clear-bottom 96-well plate, supplemented with previously frozen OP50 to avoid starvation.…”

Section: Methodsmentioning

confidence: 99%

Elevated Trehalose Levels in C. elegans daf-2 Mutants Increase Stress Resistance, Not Lifespan

et al. 2021

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The C. elegans insulin/IGF-1 signaling mutant daf-2 recapitulates the dauer metabolic signature—a shift towards lipid and carbohydrate accumulation—which may be linked to its longevity and stress resistance phenotypes. Trehalose, a disaccharide of glucose, is highly upregulated in daf‑2 mutants and it has been linked to proteome stabilization and protection against heat, cold, desiccation, and hypoxia. Earlier studies suggested that elevated trehalose levels can explain up to 43% of the lifespan extension observed in daf-2 mutants. Here we demonstrate that trehalose accumulation is responsible for increased osmotolerance, and to some degree thermotolerance, rather than longevity in daf-2 mutants. This indicates that particular stress resistance phenotypes can be uncoupled from longevity.

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Section: Methodsmentioning

confidence: 99%

Elevated Trehalose Levels in C. elegans daf-2 Mutants Increase Stress Resistance, Not Lifespan

et al. 2021

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“…The literature linking stress, innate immunity, and aging in C. elegans has long supported a simple model that stress resistance and innate immunity are linked, and that the two are inversely correlated with age [33,34]. Although recent, more detailed findings have suggested that it is not quite this simple [35], a strong correlation between stress and pathogen resistance remains. Indeed, it has been clearly demonstrated that stress-inducing compounds can promote pathogen resistance, albeit with some adverse effects on the host.…”

Section: The Activity Of Lk Molecules Is Not Mediated By Conventionalmentioning

confidence: 99%

Novel Immune Modulators EnhanceCaenorhabditis elegansResistance to Multiple Pathogens

Hummell

Revtovich

Kirienko

2020

Preprint

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Traditionally, treatments for bacterial infection have focused on killing the microbe or preventing its growth. As antimicrobial resistance becomes more ubiquitous, attention has begun to shift toward disrupting the host-pathogen interaction by improving the host defense. Using a high-throughput, fragment-based screen to identify compounds that alleviate Pseudomonas aeruginosa-mediated killing of Caenorhabditis elegans, we identified over 20 compounds that stimulated host defense gene expression. Five of these molecules were selected for further characterization. Four compounds showed little toxicity against mammalian cells or worms, consistent with their identification in a phenotypic, high-content screen. Each of the compounds activated several host defense pathways, but the pathways were generally dispensable for compound-mediated rescue in Liquid Killing, suggesting redundancy or that the activation of one or more unknown pathways may be driving compound effects. A genetic mechanism was identified for LK56, which required the Mediator subunit MDT-15/MED15 and NHR-49/HNF4 for its function. Interestingly, LK32, LK34, LK38, and LK56 also rescue C. elegans from P. aeruginosa in an agar-based assay, which uses different virulence factors and defense mechanisms. Rescue in an agar-based assay for LK38 entirely depended upon the PMK-1/p38 MAPK pathway. Three compounds, LK32, LK34, and LK56 also conferred resistance to Enterococcus faecalis, and the two lattermost, LK34 and LK56, also reduced pathogenesis from Staphylococcus aureus. This study supports a growing role for MDT-15 and NHR-49 in immune response and identifies 5 molecules that with significant potential for use as tools in the investigation of innate immunity.

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“…The literature linking stress, innate immunity, and aging in C. elegans has long supported a simple model that stress resistance and innate immunity are linked and that the two are inversely correlated with age ( 34 , 35 ). Although recent, more detailed findings have suggested that it is not quite this simple ( 36 ), a strong correlation between stress and pathogen resistance remains. Indeed, it has been clearly demonstrated that stress-inducing compounds can promote pathogen resistance, albeit with some adverse effects on the host.…”

Section: Resultsmentioning

confidence: 99%

Novel Immune Modulators Enhance Caenorhabditis elegans Resistance to Multiple Pathogens

Hummell

Revtovich

Kirienko

2021

mSphere

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Traditionally, treatments for bacterial infection have focused on killing the microbe or preventing its growth. As antimicrobial resistance becomes more ubiquitous, the feasibility of this approach is beginning to wane and attention has begun to shift toward disrupting the host-pathogen interaction by improving the host defense. Using a high-throughput, fragment-based screen to identify compounds that alleviate Pseudomonas aeruginosa-mediated killing of Caenorhabditis elegans, we identified over 20 compounds that stimulated host defense gene expression. Five of these molecules were selected for further characterization. Four of five compounds showed little toxicity against mammalian cells or worms, consistent with their identification in a phenotypic, high-content screen. Each of the compounds activated several host defense pathways, but the pathways were generally dispensable for compound-mediated rescue in liquid killing, suggesting redundancy or that the activation of unknown pathway(s) may be driving compound effects. A genetic mechanism was identified for LK56, which required the Mediator subunit MDT-15/MED15 and NHR-49/HNF4 for its function. Interestingly, LK32, LK34, LK38, and LK56 also rescued C. elegans from P. aeruginosa in an agar-based assay, which uses different virulence factors and defense mechanisms. Rescue in an agar-based assay for LK38 entirely depended upon the PMK-1/p38 MAPK pathway. Three compounds—LK32, LK34, and LK56—also conferred resistance to Enterococcus faecalis, and the two lattermost, LK34 and LK56, also reduced pathogenesis from Staphylococcus aureus. This study supports a growing role for MDT-15 and NHR-49 in immune response and identifies five molecules that have significant potential for use as tools in the investigation of innate immunity. IMPORTANCE Trends moving in opposite directions (increasing antimicrobial resistance and declining novel antimicrobial development) have precipitated a looming crisis: the nearly complete inability to safely and effectively treat bacterial infections. To avert this, new approaches are needed. One idea is to stimulate host defense pathways to improve the clearance of bacterial infection. Here, we describe five small molecules that promote resistance to infectious bacteria by activating C. elegans’ innate immune pathways. Several are effective against both Gram-positive and Gram-negative pathogens. One of the compounds was mapped to the action of MDT-15/MED15 and NHR-49/HNF4, a pair of transcriptional regulators more generally associated with fatty acid metabolism, potentially highlighting a new link between these biological functions. These studies pave the way for future characterization of the anti-infective activity of the molecules in higher organisms and highlight the compounds’ potential utility for further investigation of immune modulation as a novel therapeutic approach.

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New label‐free automated survival assays reveal unexpected stress resistance patterns during C. elegans aging

Cited by 18 publications

References 60 publications

Elevated Trehalose Levels in C. elegans daf-2 Mutants Increase Stress Resistance, Not Lifespan

Elevated Trehalose Levels in C. elegans daf-2 Mutants Increase Stress Resistance, Not Lifespan

Novel Immune Modulators EnhanceCaenorhabditis elegansResistance to Multiple Pathogens

Novel Immune Modulators Enhance Caenorhabditis elegans Resistance to Multiple Pathogens

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